AMACR amplification and overexpression in primary imatinib-naïve gastrointestinal stromal tumors: a driver of cell proliferation indicating adverse prognosis
| Autor: | Fu-Ming Fang, Yen-Yang Chen, Hui-Chun Tai, Shih-Chen Yu, Hsuan-Ying Huang, Jui Lan, Chien-Feng Li, Ching-Yih Lin, Shau-Hsuan Li, Li-Tzong Chen, Fong-Fu Chou, Tzu-Ju Chen |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Azoles
DNA Mutational Analysis Gene Dosage amplification Isoindoles Piperazines Organoselenium Compounds Cyclin D1 In Situ Hybridization Fluorescence Oncogene Proteins 5p Comparative Genomic Hybridization Tissue microarray GiST Flow Cytometry Prognosis Immunohistochemistry Up-Regulation Treatment Outcome Oncology Benzamides Imatinib Mesylate RNA Interference medicine.drug Research Paper GIST Genotype Gastrointestinal Stromal Tumors proliferation Racemases and Epimerases PDGFRA Biology Disease-Free Survival Predictive Value of Tests Cell Line Tumor Cyclin E medicine Humans Cell Proliferation G1 Phase AMACR Gene Cancer Cyclin-Dependent Kinase 4 Imatinib medicine.disease Molecular medicine Pyrimidines Multivariate Analysis Cancer research AMACR |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Chien-Feng Li 1,2,3,4 , Li-Tzong Chen 2,3,5,6 , Jui Lan 7 , Fong-Fu Chou 8 , Ching-Yih Lin 9,10 , Yen-Yang Chen 11 , Tzu-Ju Chen 1 , Shau-Hsuan Li 11 , Shih-Chen Yu 7 , Fu-Ming Fang 12 , Hui-Chun Tai 13 and Hsuan-Ying Huang 7 1 Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan 2 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan 3 Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 4 Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan 5 Department of Internal Medicine and Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 6 Institutes of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan 7 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 8 Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 9 Department of Tourism Management, Southern Taiwan University of Science and Technology, Tainan, Taiwan 10 Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan 11 Division of Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 12 Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 13 Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan Correspondence: Hsuan-Ying Huang, email: // Keywords : GIST, 5p, AMACR, amplification, proliferation Received : August 13, 2014 Accepted : October 18, 2014 Published : October 18, 2014 Abstract Non-random gains of chromosome 5p have been observed in clinically aggressive gastrointestinal stromal tumors, whereas the driving oncogenes on 5p remain to be characterized. We used an integrative genomic and functional approach to identify amplified oncogenes on 5p and to evaluate the relevance of AMACR amplification at 5p13.3 and its overexpression in gastrointestinal stromal tumors. Thirty-seven tumor samples, imatinib-sensitive GIST882 cell line, and imatinib-resistant GIST48 cell line were analyzed for DNA imbalances using array-based genomic profiling. Forty-one fresh tumor samples of various risk categories were enriched for pure tumor cells by laser capture microdissection and quantified for AMACR mRNA expression. AMACR- specific fluorescence in situ hybridization and immunohistochemistry were both informative in tissue microarray sections of 350 independent primary gastrointestinal stromal tumors, including 213 cases with confirmed KIT / PDGFRA genotypes. To assess the oncogenic functions of AMACR, GIST882 and GIST48 cell lines were stably silenced against their endogenous AMACR expression. In 59% of cases featuring 5p gains, two major amplicons encompassed discontinuous chromosomal regions that were differentially overrepresented in high-risk cases, including the one harboring the mRNA-upregulated AMACR gene. Gene amplification was detected in 19.7% of cases (69/350) and strongly related to protein overexpression (p |
| Databáze: | OpenAIRE |
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